Macroh2a1 Case Study

Its locus is particularly amplified in these noted tumours leading to the progression of these cancers, it can be suppressed by p53 (tumour/ proliferation suppressor) which represses the EZH2 promoter, resulting inhibition of cell proliferation and invasion (Bracken, 2003; Xiao, 2011).

Humans undergo several stages during their lifetime including growth, development, reproduction and senescence. Senescence is defined as the deteriorative biological changes that organisms experience as they age eventually leading to death. These changes include low metabolism, a weak immune system, memory loss, poor vision and loss of hearing. Senescence begins in humans during their post-reproductive years. However, gerontology research has shown that individuals who reproduce late have longer life spans compared to individuals who reproduce early. Nonetheless, it does not indicate that senescence is inevitable. All organisms experience senescence,

At the National Human Genome Research Institute (NHGRI) they conducted a study on age-related cell damage

Cancer cells displayed marked alterations in pro-growth signaling pathways and key metabolic pathways relative to non-tumorigenic differentiated cells, often due to loss of tumor suppressor genes and oncogenic driver mutations. The remodeled signaling and metabolic profiles of cancer cells support not only their aberrant proliferation, but also their survival. Further factors such as intra-tumoral heterogeneity, altered redox status, and epigenetic modifications all contribute to the ability of certain tumors to develop drug resistance and persist under standard treatments.

LBH589 increases histone acetylation in HD mice: We assessed histone H3 acetylation as a pharmacodynamic marker of HDAC inhibition in R6/2 mice. LBH589 has been previously demonstrated to rapidly induce histone acetylation in various tumor tissues [18]. R6/2 mice were treated with either vehicle or LBH589 at the dose rate of 20 mg/kg/three times per week for 3 weeks and the acetylation of histone H3 was determined in brain and muscle tissue by western blotting. When assessed in R6/2 mice sacrificed 2 hr after the last dose, total H3 acetylation significantly increased in brain (2.8

Mutations in the daf-2 insulin receptor?like gene or the downstream age-1 phosphoinositide 3-kinase gene extend adult lifespan by two to threefold. To identify tissues where this pathway regulates aging and metabolism, we restored daf-2 pathway signaling to only neurons, muscle, or intestine. Insulin-like signaling in neurons alone was sufficient to specify wild-type lifespan, but muscle or intestinal signaling was not. However, restoring daf-2 pathway signaling to muscle rescued metabolic defects, thus decoupling regulation of lifespan and metabolism. These findings point to the nervous system as a central regulator of animal longevity. (Wolkow et.al,

Cellular senescence has always previously thought to be an unavoidable and irreversible process wherein old cells stop dividing and undergo a series of chemical and physical changes. These bigger, flatter senescent cells do not die and accumulate in all parts of the body. Senescent cells were only associated with a body’s natural safeguard against cancer; Cells that are cancerous are often fast-tracked to senescence in hopes that it will stop dividing further. However, recent discoveries have shown that senescent cells actually pump out a variety of proteins that cause inflammation, a normally healthy immune response that damages healthy cells in the long run. Almost every discovered

Reduced health problems or occurrence of disability causing diseases is one of the major problems in ageing process besides an extended life span. Daf-2 was one of the first few genes that were discovered to be directly involved in extending the lifespan of Caenorhabditis elegans (Kenyon et al., 1993). Considerable evidence in past has been provided by the association of mitochondrial abnormalities (Trifunovic and Larsson, 2008), genetic instability, altered intercellular signaling, an imbalance in hormones and reduced cell replacement capacity as key players in regulating cellular ageing (Figure 2 A). Being a central component involved in cellular metabolism and a major factor in disease occurrence, various studies utilizing protein quality

In vitro: Previous study found that HNHA was able to inhibit in-vitro HDAC enzyme activity as well as proliferation of human fibrosarcoma cells (HT1080). In addition, treatment of cells with HNHA could elicite histone hyperacetylation resulting in an up-regulation of cell cycle arrest, p21 transcription, and an inhibition of HT1080 cell invasion [1].

Aberrant expression of p16INK4a, either high or low, is found frequently in human cancers (Table 1). In colon cancer, two different patterns of p16INK4a overexpression have been reported. The first pattern is related to senescence in serrated adenomas, which have malignant transformation associated with p16INK4a downregulation (Refs. 138, 139). The second pattern is characterized by a very low p16INK4a immunostaining in normal mucosa, with a progressively higher expression in aberrant crypt foci, non-serrated adenomas, primary carcinomas and metastatic tumors (Ref. 87). A similar pattern was observed in skin cancer where p16INK4a expression increases from relatively low levels in pre-malignant lesions to high levels in in situ and infiltrating carcinomas (Ref. 140). In breast cancer, p16INK4a was negative or low in normal ductal epithelium, but a progressive increase was found in benign lesions and carcinoma (Refs. 88, 89). Increased nuclear p16INK4a protein expression compared with normal epithelium has been reported in pre-neoplastic and tumor tissues of the gallbladder (Ref. 141). Therefore, inactivation of

These anti cancer mechanisms depend on p53 and p16ink4 activation, which appear to be responsible for aging similarly to how their failure is associated with cancer. Some other possible mechanisms include heritable mutations and environmental changes in stem cell surroundings. These assumptions are so controversial because adequate models to test the function of these cells have yet to be constructed. Therefore, there I no direct way of determining that stem cell aging is the decrease in stem cell function through regeneration degradation. However, it is an idealistic assumption due to the resulting data of stem cells from other tissues that identify the association between proliferating decline in tissue and aging. A study involving rodents identified that a decline in the quantity of neurons being produced by neural stem cells would decrease with telomere dysfunction. Senescence is a form of growth arrest that is induced by stimuli like loss of telomere function, reactive oxygen species, some DNA damage, and tumor suppressor activation.

Even though, many organisms have developed different ways to maintain the oxygen homeostasis of their body, changes in the oxygen concentrations will induce the use of other genes. During hypoxic conditions, the HIF-1, transcription factor of two subunits (β-subunit and α-subunit), is activated and with other transcription factors play a significant role in the cancer proliferation. For example, together, the HIF-1 and NFĸB, control over 1,000 genes, promote angiogenesis with VEGF, VEGF receptors, COX-2, iNOS; tissue growth factors and inhibits enzymes, stimulating the cell migration or metastasis. Also, it is important to mention that the activity of the HIF-1 will depend in the gene expression and mutation and can negatively affect the ING4, p53, PTEN, VHL genes and will promote the activity of oncogenes: Ras, Raf, Src, mTOR, and

An organism 's capacity to regulate gene expression in the response to ecological elements, for instance, nourishments levels and oxygen accessibility is basic for survival. Taking to account that sirtuin genes act to regulate protein expression by two distinct mechanisms: deacetylation of histones proteins, leading to tighter chromatin packaging and therefore decreased transcription; or deacetylation of various other proteins, leading to inactivation. The first experiment implicating sirtuin genes in aging was done in yeast cells. This experiment showed, overexpression of sir2 protein in yeast led to an increase in lifespan. From

ferocious chemistry is disable to differentiate between the cancerous cell or the healthy cell and

MacroH2A1.1-overexpressing cells display ameliorated glucose metabolism, 214 reduced expression of lipogenic genes and fatty acid content (40). These associative 215 studies indicate a possible conserved involvement of macroH2A1 isoforms, in lipid 216 metabolism. A number of mechanistic studies using animal have explored this 217 possibility, yielding conflicting outcomes (Table II). Two mouse models with a 218 macroH2A1 knockout have been reported under a standard diet feeding. In the first 219 model, generated in the pure C57Bl/6J background, developmental changes in 220 macroH2A1-mediated gene regulation were observed (42): up-regulation of 221 lipogenic genes was detected in the liver of the knockout mice (42), which displayed 222